Purification process for the preparation of non-carrier added copper-64

ABSTRACT

Compositions comprising high levels of high specific activity copper-64, and process for preparing said compositions. The compositions comprise from about 2 Ci to about 15 Ci of copper-64 and have specific activities up to about 3800 mCi copper-64 per microgram of copper. The processes for preparing said compositions comprise bombarding a nickel-64 target with a low energy, high current proton beam, and purifying the copper-64 from other metals by a process comprising ion exchange chromatography or a process comprising a combination of extraction chromatography and ion exchange chromatography.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/993,186, filed Nov. 23, 2022, which is a continuation of U.S.application Ser. No. 17/894,874, now issued as U.S. Pat. No. 11,581,103,filed Aug. 24, 2022, which is a continuation of U.S. application Ser.No. 17/446,443, now issued as U.S. Pat. No. 11,521,762, filed Sep. 3,2021, which claims the priority of U.S. Provisional Application Ser. No.63/074,356, filed Sep. 3, 2020, the disclosures of which are herebyincorporated by reference in their entirety.

FIELD

The present disclosure relates to compositions comprising high levels ofhigh specific activity copper-64, and process for preparing saidcompositions.

BACKGROUND

Diagnostic nuclear medicine uses two imaging techniques-single photonemission tomography (SPECT) and positron emission tomography (PET),often in conjunction with computerized tomography (CT) or magneticresonance imaging (MRI). Of the two imaging techniques, PET provideshigher resolution images and quantitative information. The enhancedcapabilities of PET have generated higher demand for radiopharmaceuticalagents that are capable of being imaged using this technique, thusnecessitating the production of commercial quantities of radioactiveprecursors capable of PET for routine clinical use.

Common clinically-used PET isotopes include oxygen-15 (¹⁵O), nitrogen-13(¹³N), carbon-11 (¹¹C), fluorine-18 (¹⁸F), and gallium-68 (⁶⁸Ga). Eachof these isotopes, however, has a relatively short half-life, whichnecessitates producing them in close proximity to the PET imaging deviceand incorporating them into imaging agents before excessive radioactivedecay or drug product decomposition occurs. A generator system for ⁶⁸Gais available but it can be difficult to obtain and severely limits thenumber of doses that can be prepared in a day. To address thelimitations of the short half-life radionuclides, PET isotopes withrelatively longer half-lives have been investigated for development ofnew diagnostic PET agents.

Copper-64 (⁶⁴Cu) is a ‘non-standard isotope’ that can be used indiagnostic nuclear medicine. It is a radionuclide with excellentcharacteristics for PET imaging. Its average positron energy of 278.2keV provides high resolution images, and its moderate half-life (12.7 h)is suitably long to allow for production, purification, incorporationinto a carrier molecule (e.g., peptide, small-molecule, antibody, etc.)and distribution to medical facilities as an end-use product.

For widespread availability of ⁶⁴Cu on a commercial scale, largequantities of ⁶⁴Cu (i.e., Ci or GBq amounts) must be produced andisolated in a highly pure and chemically useful form (e.g., ⁶⁴Cu copperchloride) for use as a radioactive precursor. Preparations of ⁶⁴Cucopper chloride have been produced from isotopically enriched nickel-64(⁶⁴Ni) targets, and the ⁶⁴Cu has been purified using ion exchangechromatography. In references located as of 2020, the highest reportedamount of ⁶⁴Cu produced was 1.5 Ci, reported at end of bombardment(EOB). While this amount is sufficient for preparing patient doses, whenfactoring in decay and yield loss during manufacturing (i.e.,formulation, sterilization, dispense, quality control, packaging andshipment)—1.5 Ci of ⁶⁴Cu at EOB may yield 50 patient doses in abest-case scenario (assuming an average patient dose of 4 mCi, 32 h formanufacturing and shipment and 15% yield loss). The number oftheoretical patient doses may be significantly improved by increasingthe available quantity of ⁶⁴Cu copper chloride precursor. The ⁶⁴Cu mustbe of high chemical and radionuclidic purity.

Specific activity (i.e., activity of ⁶⁴Cu per mass of total Cu) of ⁶⁴Cucopper chloride is an indicator of its chemical purity and is oftenexpressed in units of mCi/μg or Ci/mmol. In references located as of2020, the highest reported specific activity of purified ⁶⁴Cu copperchloride was 348 mCi/μg Cu. This is sufficient for radiolabeling, butimprovements in specific activity may improve the purity and reactivityof a radioactive precursor, thereby decreasing the required amount ofcarrier molecule necessary in production of a radiolabeledpharmaceutical. This has implications for patient safety and may enhancethe diagnostic capability of a radiopharmaceutical. Improvements inspecific activity of ⁶⁴Cu may be made by increasing the producedquantity of radioactive precursor, limiting the potential forintroduction of trace metallic contaminants and creating a robustpurification process.

If ⁶⁴Cu were widely available, it would enhance the capabilities ofexisting PET centers and would also allow PET studies to be performed atmedical centers that do not have an on-site ⁶⁸Ge/⁶⁸Ga generator and/ordo not rely on a regional cyclotron. Described herein are methods ofmaking purified ⁶⁴Cu having improved chemical and radionuclidic puritiesand a specific activity that is favorable for supplying commercialclinical needs of PET and medical centers.

SUMMARY

Among the various aspect of the present disclosure are compositionscomprising high levels of ⁶⁴Cu with high purity and high specificactivity and processes for preparing said compositions.

One aspect of the present disclosure provides a composition comprisingfrom about 2 Ci to about 15 Ci of ⁶⁴Cu at end of bombardment (EOB). Thecomposition is obtained from a single target during one cyclotron run.The composition has a specific activity up to about 3800 mCi ⁶⁴Cu/μg Cu.In some embodiments, the composition comprises a solution ofhydrochloric acid, such that the ⁶⁴Cu exists as [⁶⁴Cu]CuCl₂.

A further aspect of the present disclosure encompasses a process forpreparing the ⁶⁴Cu from ⁶⁴Ni. The process comprises (a) bombarding acyclotron target comprising ⁶⁴Ni with a proton beam to generate abombarded target; (b) stripping the bombarded target with a volume ofHCl having a molarity of about 6 M to about 12.1 M to form a stripsolution comprising ⁶⁴Ni and ⁶⁴Cu; and (c) purifying the ⁶⁴Cu from thestrip solution by ion exchange chromatography, wherein the ion exchangechromatography comprises (i) passing the strip solution through a columncomprising an ion exchange resin such that ⁶⁴Cu binds to the ionexchange resin and ⁶⁴Ni passes through the column as a flow-through;(ii) rinsing the column with a volume of HCl having a molarity of about3 M to about 6 M; and (iii) adding a volume of HCl having a molarity ofabout 0.5 M to about 3 M to the column to elute the ⁶⁴Cu from the ionexchange resin and collecting an eluate comprising ⁶⁴Cu.

Another aspect of the present disclosure encompasses an additionalprocess for preparing ⁶⁴Cu from ⁶⁴Ni, wherein the ⁶⁴Cu is purified by acombination of extraction chromatography and ion exchangechromatography. The process comprises (a) bombarding a cyclotron targetcomprising ⁶⁴Ni with a proton beam to generate a bombarded target; (b)stripping the bombarded target with a volume of HCl having a molarity ofabout 6 M to about 12.1 M to form a strip solution comprising ⁶⁴Ni,⁶⁴Cu, ⁶¹Co, and other or more other metals; and (c) purifying the ⁶⁴Cufrom the strip solution by chromatography, wherein the chromatographycomprises (i) passing the strip solution through a first columncomprising an extraction resin connected in series to a second columncomprising an ion exchange resin, such that the one or more other metalsbinds to the extraction resin in the first column, ⁶⁴Cu and ⁶¹Co bind tothe ion exchange resin in the second column, and ⁶⁴Ni passes throughboth columns as a first flow-through fraction. The process furthercomprises (ii) rinsing the first and second columns with a volume of HClhaving a molarity of about 6 M to about 12.1 M to remover residual ⁶⁴Nias a second flow-through fraction; (iii) rinsing the second column witha volume of HCl having a molarity of about 3 M to about 6 M to elute⁶¹Co as a first waste fraction; (iv) rinsing the second column with avolume of NaCl having a molarity of about 3 M to 6 M in HCl having amolarity of about 0.01 M to about 3 M or with a volume of HCl having amolarity of about 3 M to about 6 M to elute residual ⁶¹Co as a secondwaste fraction; and (v) adding a volume of HCl having a molarity ofabout 0.01 M to about 3 M to the second column to elute the ⁶⁴Cu as aproduct fraction comprising ⁶⁴Cu.

Other aspects and iterations of the present disclosure are detailedbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 presents a schematic of the purification process comprising ionexchange chromatography.

FIGS. 2A, 2B, and 2C present various embodiments of the purificationprocess comprising a combination of extraction chromatography and ionexchange chromatography,

FIG. 3 is a plot of proton energy as a function of proton beam radius.

DETAILED DESCRIPTION

Provided herein are compositions comprising high levels of high specificactivity ⁶⁴Cu and processes for preparing said compositions. Theprocesses disclosed herein are able to produce high levels of ⁶⁴Cu froma single target during one continuous cyclotron bombardment (i.e.,cyclotron run). The ⁶⁴Cu produced by these processes has a high specificactivity, as well as high chemical and radionuclidic purities.Favorably, the ⁶⁴Cu compositions produced by the processes disclosedherein also have low levels of metal impurities such as cobalt, iron,nickel and lead.

(I) Compositions

The ⁶⁴Cu compositions disclosed herein comprise high levels of highspecific activity ⁶⁴Cu. In general, the ⁶⁴Cu compositions comprise up toabout 15 Ci of ⁶⁴Cu and have specific activities up to about 3800 mCi⁶⁴Cu/μg Cu. The ⁶⁴Cu compositions may be prepared by the processesdescribed below in sections (II) and (III).

The ⁶⁴Cu activity (Ci or Bq) may be measured by gamma spectroscopy(e.g., high purity germanium (HPGe) detector), a dose calibrator, orsimilar means. Specific activity (mCi ⁶⁴Cu/μg Cu) may be determined bymeasuring the mass of Cu by a variety of methods including inductivelycoupled plasma optical emission spectroscopy (ICP-OES), inductivelycoupled plasma mass spectrometry (ICP-MS), or titration.

In general, the compositions disclosed herein comprise from about 2 Cito about 15 Ci of ⁶⁴Cu at the end of bombardment (EOB). The level of⁶⁴Cu may be determined at EOB or a later time point. Persons skilled inthe art understand that the level of ⁶⁴Cu activity decreases over time.In some embodiments, the compositions may comprise from about 2 Ci toabout 3 Ci, from about 3 Ci to about 4 Ci, from about 4 Ci to about 5Ci, from about 5 Ci to about 6 Ci, from about 6 Ci to about 7 Ci, fromabout 7 Ci to about 8 Ci, from about 8 Ci to about 9 Ci, from about 9 Cito about 10 Ci, from about 10 Ci to about 11 Ci, from about 11 Ci toabout 12 Ci, from about 12 to about 13 Ci, from about 13 to about 14, orfrom about 14 to about 15 Ci of ⁶⁴Cu. In other embodiments, thecomposition may comprise from about 4.0-4.5 Ci, from about 4.5-5.0 Ci,from about 5.0-5.5 Ci, from about 5.5-6.0 Ci, from about 6.0-6.5 Ci,from about 6.5-7.0 Ci, from about 7.0-7.5 Ci, from about 7.5-8.0 Ci,from about 8.0-8.5 Ci, from about 8.5-9.0 Ci, from about 9.0-12.0, fromabout 12.0-15.0, from about 4.0-5.5 Ci, from about 5.5-7.0 Ci, fromabout 6.0-7.5 Ci, from about 7.0-8.5 Ci, r from about 7.5-9.0 Ci, orfrom about 9.0-15.0 Ci of ⁶⁴Cu.

In other embodiments, the compositions may comprise from about 2 Ci toabout 5 Ci of ⁶⁴Cu at EOB, from about 5 Ci to about 9 Ci of ⁶⁴Cu at EOB,or from about 9 Ci to about 15 Ci at EOB. In further embodiments, thecompositions may comprise from about 2 Ci to about 5 Ci of ⁶⁴Cu (at EOB)after about 2-4 h of bombardment, or about 5 Ci to about 9 Ci of ⁶⁴Cu(at EOB) after about 6 h of bombardment, or about 4 Ci to about 15 Ci of⁶⁴Cu (at EOB) after about 8-12 h of bombardment.

Each of the compositions disclosed herein may be produced during asingle cyclotron run and/or may be obtained from a single cyclotronbombardment.

The radionuclidic purity of the ⁶⁴Cu compositions disclosed herein isgenerally greater than about 98.5%, greater than about 99%, greater thanabout 99.5%, or greater than about 99.9% (referenced at 6 am of the dayafter bombardment).

The specific activity of the ⁶⁴Cu in the compositions disclosed hereinmay be as high as about 3800 mCi ⁶⁴Cu/μg Cu at EOB. Those skilled in theart understand that the specific activities of the compositions decreaseover time. In various embodiments, the specific activity may range fromabout 100 mCi ⁶⁴Cu/μg Cu to about 500 mCi ⁶⁴Cu/μg Cu, from about 500 mCi⁶⁴Cu/μg Cu to about 1000 mCi ⁶⁴Cu/μg Cu, from about 1000 mCi ⁶⁴Cu/μg Cuto about 1500 mCi ⁶⁴Cu/μg Cu, from about 1500 mCi ⁶⁴Cu/μg Cu to about2500 mCi ⁶⁴Cu/μg Cu, from about 2500 mCi ⁶⁴Cu/μg Cu to about 3000 mCi⁶⁴Cu/μg Cu, or from about 3000 mCi ⁶⁴Cu/μg Cu to about 3800 mCi ⁶⁴Cu/μgCu. In some embodiments, the specific activity may range from about 350⁶⁴Cu/μg Cu to about 2300 mCi ⁶⁴Cu/μg Cu. In further embodiments, thespecific activity may range from about 350 ⁶⁴Cu/μg Cu to about 500 mCi⁶⁴Cu/μg Cu at EOB, from about 500 ⁶⁴Cu/μg Cu to about 1000 mCi ⁶⁴Cu/μgCu at EOB, or from about 1000 ⁶⁴Cu/μg Cu to about 2300 mCi ⁶⁴Cu/μg Cu atEOB.

In general, the ⁶⁴Cu compositions disclosed herein comprise low levelsof metal contaminants. The metal contaminants may be radioactive ornonradioactive. The metal contaminants may include calcium, cobalt,copper, gold, iron, lead, mercury, nickel, and zinc. For example, the 2M HCl eluate described below in Example 5 comprises 0 ppm Au, 0 ppm Hg,<0.02 ppm Co, <0.2 ppm Fe, <0.4 ppm Pb, <0.5 ppm Ni, <0.6 ppm Cu, and<1.5 ppm Zn. In general, the ⁶⁴Cu compositions disclosed herein compriseless than about less than about 6 ppm total, less than about 5 ppmtotal, less than about 4 ppm total, or less than about 3 ppm total ofcobalt, copper, gold, iron, lead, mercury, nickel, and zinc.

The ⁶⁴Cu compositions disclosed herein may comprise a solution ofhydrochloric acid (HCl) such that the solution comprises [⁶⁴Cu]CuCl₂.The solution of HCl may comprise from about 0.005 M to about 3.0 M ofHCl. In some embodiments, the solution of HCl may comprise HCl at amolarity from about 0.01 M to about 2.0 M, from about 0.02 M to about1.0 M, or from 0.04 M to about 0.06 M. In specific embodiments, the ⁶⁴Cucompositions may comprise a solution of about 0.05 M HCl.

In some embodiments, the compositions disclosed herein may furthercomprise at least one bifunctional chelating agent such that the coppermay complex with the bifunctional chelating agent. The bifunctionalchelating agent may be a macrocyclic compound, a bridged macrocycliccompound, a bicyclic compound, or an acyclic compound. Examples ofsuitable bifunctional chelating agents include1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA),1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA),1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N′″-tetraacetic acid (TETA),5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoicacid (MeCOSar),5-((8-amino-3,6,10,13,16,19-hexaazabicyclo(6.6.6)eicos-1-yl)amino)-5-oxopentanoicacid (sar-CO2H), di- and trimethylthiazolyl 1,4,7-triazacyclononane(TACN), diethylenetriaminepentaacetic acid (DTPA),3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), analogs, or derivativesthereof. In specific embodiments, the bifunctional chelating agent maybe DOTA. The bifunctional chelating agent may be linked to a celltargeting agent such as a peptide, protein, antibody, or fragmentthereof.

(II) Processes for Producing Copper-64—Purification by Ion ExchangeChromatography

Also provided herein are processes for preparing ⁶⁴Cu from ⁶⁴Ni, whereinthe ⁶⁴Cu has high specific activity, high chemical purity, and highradionuclidic purity. ⁶⁴Cu is formed when a ⁶⁴Ni nucleus captures aproton and then emits a neutron as shown in the following reaction,⁶⁴Ni+p→⁶⁴Cu+n. Proton-induced production of ⁶⁴Cu occurs in a cyclotron.The processes disclosed herein are “non-carrier added” in that noinactive material or carrier is intentionally added during theproduction process.

The processes disclosed herein are able to produce ⁶⁴Cu in high yieldand with high specific activity in one cyclotron run. Stated anotherway, high yield and high specific activity compositions comprising ⁶⁴Cuare obtainable from a single cyclotron target during one cyclotron run.Depending upon the various parameters, yields as high as about 40 Ci of⁶⁴Cu may be achieved using the processes disclosed herein.

The production process comprises bombarding a ⁶⁴Ni target with a protonbeam such that ⁶⁴Cu is produced, and cobalt-61 (⁶¹Co) is produced as aby-product. The next step of the process comprises stripping the metalsfrom the bombarded target with a strong acid (e.g., 6 M to about 12.1 MHCl) to form a strip solution. The last step of the production processcomprises purifying the ⁶⁴Cu by ion exchange chromatography. The ionexchange chromatography process comprises (i) passing the strip solutionthrough a column comprising an ion exchange resin such that ⁶⁴Cu bindsto the ion exchange resin and ⁶⁴Ni passes through the column as aflow-through, (ii) rinsing the column with a volume of HCl having amolarity of about 3 M to about 6 M and (iii) adding a volume of HClhaving a molarity of about 0.5 M to about 3 M to the column to elute the⁶⁴Cu from the ion exchange resin and collecting an eluate comprising⁶⁴Cu. FIG. 1 presents a schematic of an iteration of the process.

(a) Bombarding the Target

The proton-induced production of ⁶⁴Cu via a ⁶⁴Ni target occurs in acyclotron. Suitable cyclotrons include low-energy cyclotrons (e.g., 3-20MeV energy range) and medium-energy cyclotrons (e.g., 15-30 MeV range).The targets of said cyclotrons may be curved or flat. As detailed inExample 3 below, the present disclosure reveals that cyclotron targetsmay be bombarded at high currents with approximately 12 MeV to 13 MeVprotons.

The cyclotron target may comprise a copper base layer that has beenelectroplated with gold to a thickness of about 50 μm. The gold-platedcyclotron target then may be plated with enriched ⁶⁴Ni. The ⁶⁴Ni may beenriched to about 98%, about 99%, about 99.6%, or about 99.9% ⁶⁴Ni. Thetargeting mass of enriched ⁶⁴Ni may range from about 40 mg to about 60mg, from about 45 mg to about 55 mg, from about 48 mg to about 52 mg, orabout 50 mg. The plating area may range from about 3.0 cm² to about 5.0cm², from about 3.2 cm² to about 4.8 cm², from about 3.6 cm² to about4.4 cm², from about 3.8 cm² to about 4.2 cm², or 4.0 cm². The platedlayer of ⁶⁴Ni may have a thickness from about 8 μm to about 20 μm, fromabout 10 μm to about 18 μm, from about 12 μm to about 16 μm, or about 14μm.

In the processes disclosed herein, the ⁶⁴Ni target area is bombardedwith low energy protons to produce ⁶⁴Cu. In general, the proton beam ofthe cyclotron is adjusted to have an energy of less than about 20 MeV onthe target. In some embodiments, the energy of the proton beam at thetarget can range from about 5 MeV to about 20 MeV, from about 7 MeV toabout 17 MeV, from about 10 MeV to about 15 MeV, from about 11 MeV toabout 14 MeV, from about 10 MeV to about 14 MeV, from about 11 MeV toabout 12 MeV, or from about 12 MeV to about 13 MeV. In specificembodiments, the actual beam energy at the target is about 12 MeV.

The current of the proton beam may range up to about 250 μA. In someembodiments, the current of the proton beam may range from about 10 μAto about 30 μA, about 30 μA to about 100 μA, from about 100 μA to about175 μA, or from about 175 μA to about 250 μA. In specific embodiments,the current of the proton beam may range from about 190 μA to about 230μA, or from about 200 μA to about 225 μA.

The proton beam hits the target area at an angle. In some embodiments,the angle of the proton beam may range from about 1° to about 20°, fromabout 2° to about 10°, from 2° to about 8°, from about 3° to about 6°,or about 4°. In other embodiments, the angle of the proton beam may betangential to the target area.

In some embodiments, the target radius of the proton beam may range fromabout 24 cm to about 32 cm, from about 26 cm to about 30 cm, from about27 cm to about 29 cm, or about 28 cm. In certain embodiments, the targetradius of the proton beam may be about 27.9 cm. In some embodiments, theproton beam may strike about 20-25%, about 15-30%, or about 10-35% ofthe entire target face. In other embodiments, the total area covered bythe beam may range from about 1 cm² to about 16 cm², from about 2 cm² toabout 8 cm², from about 3 cm² to about 6 cm², or from about 3.5 cm² toabout 4.5 cm². In still other embodiments, the total area covered by thebeam may be about 3.0 cm², about 3.5 cm², about 4.0 cm², about 4.5 cm²,about 5.0 cm², or about 6.0 cm².

The time of bombardment may range from about 0.5 h to about 24 h. Insome embodiments, the time of bombardment may range from 0.5 h to about8 h, from about 8 h to about 16 h, or from about 16 h to about 24 h. Inother embodiments, the bombardments time may range from 1 h to about 8h, from about 2 h to about 8 h, from about 4 h to about 8 h, from about5 h to about 8 h, or about from 5 h to about 7 h. In certainembodiments, the bombardment time may range from about 1 h to about 6 h,from about 2 h to about 6 h, from about 3 h to about 6 h, from about 4 hto about 6 h, or from about be about 5 h to about 6 h. In otherembodiments, the time of bombardment may be less than 8 h, less than 7.5h, less than 7 h, less than 6.5 h, less than 6 h, less than 5.5 h, lessthan 5.0 h, less than 4.5 h, or less than 4 h. In further embodiments,the time of bombardment may be about 1 h, about 2 h, about 3 h, about 4h, about 5 h, about 6 h, about 7 h, or about 8 h. In specificembodiments, the time of bombardment may range from about 2 h to about 4h or the time of bombardment may be about 6 h.

In specific embodiments, a cyclotron target comprising 50 mg ⁶⁴Ni isbombarded with a proton beam having an energy of about 12 MeV and a beamcurrent of 200 μA or 225 μA for about 1 h, 2 h, 3 h, 4 h, or 6 h.

The bombarded target may comprise from about 2 Ci to about 15 Ci of ⁶⁴Cuat the end of bombardment (EOB). The bombarded target also comprisesunreacted ⁶⁴Ni and ⁶¹Co that is also produced during the bombardmentprocess. In various embodiments, the bombarded target may comprise fromabout 2 Ci to about 3 Ci, from about 3 Ci to about 4 Ci, from about 4 Cito about 5 Ci, from about 5 Ci to about 6 Ci, from about 6 Ci to about 7Ci, from about 7 Ci to about 8 Ci, from about 8 Ci to about 9 Ci of⁶⁴Cu, from about 9 Ci to about 10 Ci, from about 10 Ci to about 11 Ci,from about 11 Ci to about 12 Ci, from about 12 to about 13 Ci, fromabout 13 to about 14 Ci, or from about 14 to about 15 Ci of ⁶⁴Cu. Ingeneral, longer bombardment times will yield higher levels of ⁶⁴Cu. Forexample, bombardment times of about 2 h to about 4 h may yield about 2Ci to about 5 Ci of ⁶⁴Cu at EOB, bombardments times of about 6 h mayyield about 5 Ci to about 9 Ci of ⁶⁴Cu at EOB, and bombardment times ofabout 12 h may yield about 7 Ci to about 15 Ci of ⁶⁴Cu at EOB. Ingeneral, the processes disclosed herein may produce from about 1 Ci/h toabout 1.5 Ci/h of bombardment with proton beam having an energy of about12 MeV and a current up to about 225 μA.

(b) Stripping the Bombarded Target

The next step of the process comprises stripping the ⁶⁴Ni, ⁶⁴Cu, ⁶¹Co,and other metals from the bombarded target. The metals are stripped fromthe target with a strong acid having a pKa of less than 1. Suitablestrong acids include hydrochloric acid, nitric acid, hydrobromic acid,and sulfuric acid. In some embodiments, the bombarded target is strippedwith HCl having a molarity from about 6 M to about 12.1 M (concentratedHCl). For example, the bombarded target may be stripped with about 6 MHCl, about 7 M HCl, about 8 M HCl, about 9 M HCl, about 10 M HCl, about11 M HCl, or about 12.1 M HCl. In specific embodiments, the bombardedtarget is stripped with about 9 M HCl.

The stripping may comprise adding a volume of the strong acid to achamber or holding vessel comprising the bombarded target, wherein thetarget is heated to a temperature from about 65° C. to about 100° C. Inparticular embodiments, the stripping is conducted at a temperature ofabout 75° C. After about 3-5 minutes, the acid may be removed and savedas the first strip solution. The target may be contacted with the strongacid several more times, and the resultant solutions combined with thefirst strip solution. The chamber holding the target then may be rinsedwith the strong acid, and the rinse may be combined with the stripsolutions to from the final strip solution. In particular embodiments,the bombarded target may be exposed three times with about 3 mL ofstrong acid (e.g., 9 M HCl) to generate a strip solution ofapproximately 9 mL.

In some embodiments, the strip solution may be evaporated to dryness ora small volume and the residue may be reconstituted in HCl of thedesired molarity (e.g., 9 M) for column chromatography.

In specific embodiments, the stripping comprises contacting thebombarded target with several aliquots of 9 M HCl, at a temperature ofabout 65° C. to about 100° C., and collecting the aliquots as the stripsolution. The chamber holding the bombarded target may be rinsed with 9M HCl, and the rinse combined with the strip solution.

(c) Purifying ⁶⁴Cu by Ion Exchange Chromatography

The process further comprises isolating the ⁶⁴Cu from the other metalsin the strip solution by ion exchange chromatography. In general, theion exchange chromatography utilizes a strong anion exchange resin.Strong anion exchange resins generally comprise quaternary ammoniumgroups. For example, a strong anion exchange resin may comprise trialkylammonium chloride (e.g., trialkylbenzyl ammonium or trimethylbenzylammonium) surface groups or dialkyl 2-hydroxyethyl ammonium chloride(e.g., dimethyl-2-hydroxyethylbenzyl ammonium) surface groups. Examplesof suitable strong anion exchange resins comprising trimethylbenzylammonium groups include AG® 1-X8 (available from Bio-Rad) and Dowex® 1X8resin. In specific embodiments, the strong anion exchange resin may beAG® 1-X8, 100-200 mesh, chloride form.

A variety of columns sizes and bed volumes may be used to purify ⁶⁴Cufrom the other metals in the strip solution. This process was developedto effectively isolate ⁶⁴Cu generated from about 50 mg of ⁶⁴Ni targetmaterial, using about 4.5 g of strong anion exchange resin in a columnhaving an inner diameter of about 1 cm. It is understood that the amountof strong anion exchange resin may range from about 4.0 g to about 5.0 gand the inner diameter of the column may range from about 0.7 cm toabout 1.25 cm without departing from the scope of the disclosure.Similarly, the volumes of the eluents passed through the column may varydepending upon the size and volume of the column and/or the amount of⁶⁴Ni target material. In general, the ion exchange column isequilibrated with HCl (e.g., 9 M HCl) prior to the chromatographyprocess.

(i) Removing ⁶⁴Ni

The ion exchange separation process comprises passing the strip solutionto the prepared ion exchange column, as well as an additional 1 mL of 9M HCl used to rinse the holding vessel. The strip solution may be addedin multiple smaller aliquots (e.g., 3×3 mL, 2×4.5 mL, etc.) or the stripsolution may be added all at once. The Ni in the strip solution does notbind to the strong anion exchange resin and passes through the column,while Cu and Co and other metals bind to the strong anion exchangeresin. The column flow through may be collected as a Ni recoveryfraction. The column may be rinsed with an additional volume of HClhaving the same molarity as that of the strip solution to completelyremove any residual Ni from the column. For example, the column may berinsed with about 10 mL of 9 M HCl. The 10 mL may be added in multiplesmaller aliquots (e.g., 5×2 mL, 3×3.333 mL, etc.) or the 10 mL may beadded all at once. The column flow through from the rinse may becollected and combined with the original Ni recovery fraction. Thecombined Ni recovery fraction may be further processed to recover the⁶⁴Ni, which then may be recycled and used for plating additionalcyclotron targets. Nickel recovery processes are well known in the art.On average, about 82% of the target ⁶⁴Ni present in the strip solutionmay be recovered from the Ni recovery fraction. In various embodiments,the percentage of ⁶⁴Ni recovered in the recovery fraction may range fromabout 40% to about 99% of the starting ⁶⁴Ni.

(ii) Removing ⁶¹Co

The ion exchange purification process further comprises adding a volumeof HCl having a molarity from about 3 M to about 6 M to the ion exchangecolumn to elute ⁶¹Co. In various embodiments, a volume of 3 M HCl, 4 MHCl, 5 M HCl, or 6 M HCl may be added to the ion exchange column. Inspecific embodiments, a volume of 4 M HCl may be added to the ionexchange column. For example, about 10 mL of 4 M HCl may be added to thecolumn. The eluent may be added in smaller aliquots (e.g., 5×2 mL,3×3.33 mL, etc.) or as a bolus. The column eluate may be collected as awaste fraction that mainly comprises ⁶¹Co.

(iii) Isolating ⁶⁴Cu

The purification process further comprises adding a volume of HCl havinga molarity from about 0.5 M to about 3 M to the ion exchange column toelute the ⁶⁴Cu. In certain embodiments, a volume of 0.5 HCl, 1 M HCl, 2MHCl, or 3 M HCl may be added to the ion exchange column. In specificembodiments, the ⁶⁴Cu may be eluted from the ion exchange column with avolume of 2 M HCl. For example, about 8 mL to about 20 mL of 2 M HCl maybe added to the column. The eluent may be added in smaller aliquots(e.g., 4×2 mL, 4×5 mL, etc.) or as a bolus. The eluate comprising ⁶⁴Cuis collected as the product of the process. On average, about 80% of the⁶⁴Cu present in the strip solution may be recovered in the eluatecomprising ⁶⁴Cu. In various embodiments, the percentage of ⁶⁴Curecovered in the eluate comprising ⁶⁴Cu may range from about 60% toabout 100%. The ⁶⁴Cu in the eluate exists as [⁶⁴Cu]CuCl₂.

The final eluate comprising ⁶⁴Cu may be evaporated to dryness (or to asmaller volume) and the resultant residue may be reconstituted in avolume of HCl having a molarity about 0.001 M to about 1 M. In variousembodiments, the residue may be reconstituted in HCl having a molarityfrom about 0.005 M to about 0.5 M, from about 0.010 M to about 0.2 M,from about 0.025 M to about 0.1 M, or from about 0.04 M to about 0.06 M.In specific embodiments, the residue may be reconstituted in 0.05 M HClto form a final product comprising ⁶⁴Cu.

The ⁶⁴Cu compositions prepared by the processes disclosed herein aredescribed above in section (I).

(iv) Exemplary Ion Exchange Chromatography Purification Process

The 9 M HCl strip solution is passed through the ion exchange column,wherein ⁶⁴Cu and ⁶¹Co bind to the resin and ⁶⁴Ni flows through thecolumn. The column is rinsed with 9M HCl to remove residual ⁶⁴Ni. Theinitial column flow through and the 9 M HCL rinse can be combined as theNi recovery fraction. The column is rinsed with 4 M HCl to elute the⁶¹Co, which is a waste fraction. Lastly, the ⁶⁴Cu is eluted from thecolumn with 2 M HCl.

(III) Processes for Producing Copper-64—Purification by ExtractionChromatography and Ion Exchange Chromatography

Another aspect of the present disclosure encompasses an additionalprocess for purifying the ⁶⁴Cu from other metals in the strip solutionby a combination of extraction chromatography and ion exchangechromatography. The process comprises (a) bombarding a cyclotron targetcomprising ⁶⁴Ni with a proton beam to generate a bombarded target; (b)stripping the bombarded target with a volume of HCl having a molarity ofabout 6 M to about 12.1 M to form a strip solution comprising ⁶⁴Ni,⁶⁴Cu, ⁶¹Co, and other metals; and (c) purifying the ⁶⁴Cu from the stripsolution by chromatography, wherein the chromatography comprises (i)passing the strip solution through a first column comprising anextraction resin connected in series to a second column comprising anion exchange resin such that the one or more metals (e.g., cationiciron) binds to the extraction resin in the first column, the ⁶⁴Cu and⁶¹Co bind to the ion exchange resin in the second column, and ⁶⁴Nipasses through both columns as a first flow-through fraction; (ii)rinsing the first and second columns with a volume of HCl having amolarity of about 6 M to about 12.1 M to remove residual ⁶⁴Ni as asecond flow-through fraction; (iii) rinsing the second column with avolume of HCl having a molarity of about 3 M to about 6 M to elute ⁶¹Coas a first waste fraction; (iv) rinsing the second column with a volumeof NaCl having a molarity of about 3 M to 6 M in HCl having a molarityof about 0.01 M to about 3M to elute residual ⁶¹Co as a second wastefraction or rinsing the second column with an additional volume of HClhaving a molarity of about 3 M to about 6 M to elute ⁶¹Co as a secondwaste fraction; and (v) adding a volume of HCl having a molarity ofabout 0.01 M to about 3 M to the second column to elute the ⁶⁴Cu as aproduct fraction comprising ⁶⁴Cu. FIGS. 2A, 2B, and 2C presentschematics or several embodiments of the dual chromatographypurification process.

(a) Bombarding the Target

Suitable cyclotrons and cyclotron targets are described above in section(II)(a). The cyclotron target may comprise a copper base layer that hasbeen electroplated with gold to a thickness of about 50 μm. Thegold-plated cyclotron target then may be plated with enriched ⁶⁴Ni. The⁶⁴Ni may be enriched to about 98%, about 99%, about 99.6%, or about99.9% ⁶⁴Ni. The targeting mass of enriched ⁶⁴Ni may range from about 675mg to about 825 mg, from about 700 mg to about 800 mg, from about 720 mgto about 780 mg, or about 750 mg. The plating area may range from about17.3 cm² to about 28.8 cm², from about 18.4 cm² to about 27.6 cm², fromabout 20.7 cm² to about 25.3 cm², from about 21.8 cm² to about 24.2 cm²,from about 22.0 cm² to about 24.0 cm², or about 23.0 cm². The platedlayer of ⁶⁴Ni may have a thickness from about 21 μm to about 53 μm, fromabout 26 μm to about 48 μm, from about 32 μm to about 42 μm, or about 37μm.

In the processes disclosed herein, the ⁶⁴Ni target area is bombardedwith low energy protons to produce ⁶⁴Cu. In general, the proton beam ofthe cyclotron is adjusted to have an energy of less than about 20 MeV onthe target. In some embodiments, the energy of the proton beam at thetarget can range from about 5 MeV to about 20 MeV, from about 7 MeV toabout 18 MeV, from about 9 MeV to about 16 MeV, from about 10 MeV toabout 15 MeV, from about 11 MeV to about 14 MeV, from about 12 MeV toabout 13 MeV, or from about 12 MeV to about 14 MeV. In specificembodiments, the actual beam energy at the target is about 12 MeV.

The current of the proton beam may range up to about 408 μA. In someembodiments, the current of the proton beam may range from about 100 μAto about 150 μA, from about 150 μA to about 200 μA, from about 200 μA toabout 250 μA, from about 250 μA to about 300 μA, from about 300 μA toabout 350 μA, or from about 350 μA to about 410 μA, from about 405 μA toabout 410 μA, or about 408 μA. In specific embodiments, the current ofthe proton beam may range from about 325 μA to about 375 μA, or fromabout 350 μA to about 408 μA.

The proton beam hits the target area at an angle. In some embodiments,the angle of the proton beam may range from about 1° to about 20°, fromabout 2° to about 10°, from 2° to about 8°, from about 3° to about 6°,or about 5°. In other embodiments, the angle of the proton beam may betangential to the target area.

In some embodiments, the beam strike has an elliptic shape with minorand major axes. The minor axes may range from about 25.8 mm to about34.2 mm, from about 27.9 mm to about 32.1 mm, from about 28.8 mm toabout 31.2 mm, or about 30.0 mm. The major axes may range from about84.4 mm to about 63.6 mm, from about 79.2 mm to about 68.8 mm, fromabout 77.0 mm to about 71.0 mm, or about 74.0 mm. In certainembodiments, the minor and major axis of the elliptic beam strike may beabout 30.0 mm and 74.0 mm, respectively. In some embodiments, the protonbeam may strike about 70-80%, about 60-90%, or about 55-95% of theentire target face. In other embodiments, the total area covered by thebeam may range from about 14.0 cm² to about 30.0 cm², from about 28.0cm² to about 16.0 cm², from about 26.0 cm² to about 18.0 cm², or fromabout 25.0 cm² to about 20.0 cm², or 23.0 cm².

The time of bombardment may range from about 0.5 h to about 24 h. Insome embodiments, the time of bombardment may range from 0.5 h to about8 h, from about 8 h to about 20 h, or from about 20 h to about 24 h. Inother embodiments, the bombardment time may range from 1 h to about 24h, from about 2 h to about 24 h, from about 4 h to about 24 h, fromabout 5 h to about 24 h, or about from 5 h to about 23 h. In certainembodiments, the bombardment time may range from about 1 h to about 19h, from about 2 h to about 19 h, from about 3 h to about 19 h, fromabout 4 h to about 19 h, or from about 5 h to about 19 h. In otherembodiments, the time of bombardment may be less than 19 h, less than 18h, less than 17.5 h, less than 17 h, less than 16.5 h, less than 16 h,less than 15.5 h, or less than 15 h. In further embodiments, the time ofbombardment may be about 8 h, about 9 h, about 10 h, about 11 h, about12 h, about 13 h, about 14 h, or about 15 h. In specific embodiments,the time of bombardment may range from about 1 h to about 12 h or thetime of bombardment may be about 12 h.

In some embodiments, a target comprising about 750 mg ⁶⁴Ni may bebombarded with a proton beam having an energy of about 12 MeV to about14 MeV and a beam current of about 350 μA to about 408 μA for about 10h, 12 h, 14 h, 16 h, or 19 h. In specific embodiments, two targets eachcomprising about 750 mg ⁶⁴Ni may be bombarded simultaneously with aproton beam having an energy of about 12 MeV to about 14 MeV and a beamcurrent, incident on each target, of about 350 μA to about 408 μA forabout 10 h, 12 h, 14 h, or 19 h.

The bombarded target may comprise from about 58 Ci to about 80 Ci of⁶⁴Cu at the end of bombardment (EOB). The bombarded target alsocomprises unreacted ⁶⁴Ni and ⁶¹Co that are produced during thebombardment process. In various embodiments, the bombarded target maycomprise from about 38 Ci to about 52 Ci, from about 43 Ci to about 59Ci, from about 48 Ci to about 66 Ci, from about 52 Ci to about 72 Ci,from about 56 Ci to about 77 Ci, or from about 58 Ci to about 80 Ci of⁶⁴Cu. In general, longer bombardment times will yield higher levels of⁶⁴Cu. For example, bombardment times of about 12 h to about 16 h mayyield about 43 Ci to about 72 Ci of ⁶⁴Cu at EOB, and bombardments timesof about 19 h may yield about 58 Ci to about 80 Ci of ⁶⁴Cu at EOB. Ingeneral, the processes disclosed herein may produce from about 3.3 Ci/hto about 3.8 Ci/h of bombardment with proton beam having an energy ofabout 13 MeV and a current of about 350 μA or about 408 μA.

(b) Stripping the Bombarded Target

The next step of the process comprises stripping metals from thebombarded target. The metals are stripped from the target with a strongacid having a pKa of less than 1. Suitable strong acids includehydrochloric acid, nitric acid, hydrobromic acid, and sulfuric acid. Insome embodiments, the bombarded target is stripped with HCl having amolarity from about 6 M to about 12.1 M. For example, the bombardedtarget may be stripped with about 6 M HCl, about 7 M HCl, about 8 M HCl,about 9 M HCl, about 10 M HCl, about 11 M HCl, or about 12.1 M HCl. Inspecific embodiments, the bombarded target is stripped with about 9 MHCl.

The stripping may comprise adding a volume of the strong acid to achamber or holding vessel comprising the bombarded target, wherein thetarget is heated to a temperature from about 65° C. to about 100° C. Inparticular embodiments, the stripping is conducted at a temperature ofabout 75° C. After about 3-5 minutes, the acid may be removed and savedas the first strip solution. The target may be contacted with the strongacid several more times, and the resultant solutions combined with thefirst strip solution. The chamber holding the target then may be rinsedwith the strong acid, and the rinse may be combined with the stripsolutions to from the final strip solution. In particular embodiments,the bombarded target and the holding chamber may be contacted severaltimes with aliquots (e.g., 5-10 mL) of the strong acid (e.g., HCl) togenerate a final strip solution of approximately 20 mL to 40 mL.

In specific embodiments, the stripping comprises contacting thebombarded target with several aliquots of 9 M HCl, at a temperature ofabout 65° C. to about 100° C., and collecting the aliquots as the stripsolution. The chamber holding the bombarded target may be rinsed with 9M HCl, and the rinse combined with the strip solution. The stripsolution comprises ⁶⁴Ni, ⁶⁴Cu, ⁶¹Co, and can contain other metals (e.g.,Fe).

(c) Purifying ⁶⁴Cu by Extraction Chromatography and Ion ExchangeChromatography

The last step of the process comprises purifying ⁶⁴Cu from the othermetals in the strip solution by two chromatography columns. The processcomprises passing the strip solution through two columns connected inseries, the first column comprising an extraction resin and the secondcolumn comprising an ion exchange resin.

Extraction chromatography resins generally comprise macroporous polymersthat hold an organic complexing compound or extractant within the porestructure of the polymer. Suitable extraction chromatography extractantsinclude tributylphosphate (TBP), carbamoyl-methylphosphine oxide (CMPO),di-(2-ethylhexyl)-phosphoric acid (D2EHPA), and dipentylpentylphosphonate (DP[PP]). In some embodiments, the extractionchromatography extractant may be a mixture of CMPO and TBP (e.g., TRUresin; TrisKem). In specific embodiments, the extraction chromatographyextractant is TBP. An example of a suitable impregnated macroporouspolymer (i.e., resin) containing TBP is TrisKem TBP resin. In specificembodiments, the extraction resin may be TBP resin, 100-150 mesh, and inthe chloride form.

The ion exchange column comprises a weak anion exchange resin. Weakanion exchange resins generally comprise polystyrene or polyacrylicester frames that contain a primary, secondary, or tertiary amino groupas the functional group. Suitable weak anionic functional groups includediethyl aminoethyl (DEAE) and dimethyl aminoethyl (DMAE). Examples ofsuitable weak anion exchange resins comprising tertiary ammonium groupsinclude AmberLite™ FPA53 (available from Dupont) and TrisKem TK201resin. In specific embodiments, the weak anion exchange resin is TK201resin, 50-100 mesh, and in the chloride form.

A variety of columns sizes and bed volumes may be used to purify ⁶⁴Cufrom the other metals in the strip solution. This process was developedto effectively isolate ⁶⁴Cu generated from about 750 mg of ⁶⁴Ni targetmaterial, using two distinct columns, containing extraction and weakanion exchange resins, connected in series. The first column comprisesabout 300 mg of extraction resin in a column having an inner diameter of0.5 cm. It is understood that the amount of extraction resin may rangefrom about 270 mg to about 330 mg and the inner diameter of the columnmay range from about 0.4 cm to about 0.6 cm without departing from thescope of the disclosure. The second column uses about 2.7 g of weakanion exchange resin in a column having an inner diameter of about 1 cm.It is understood that the amount of weak anion exchange resin may rangefrom about 2.4 g to about 3.0 g and the inner diameter of the column mayrange from about 0.7 cm to about 1.25 cm without departing from thescope of the disclosure. Similarly, the volumes of the eluents passedthrough the column may vary depending upon the size and volume of thecolumn and/or the amount of ⁶⁴Ni target material. In general, thecolumns containing extraction resin and ion exchange resin areequilibrated with HCl (e.g., 9 M HCl) prior to the chromatographyprocess.

(i) Removing Cationic Fe and ⁶⁴Ni

The separation process comprises adding the strip solution to theprepared extraction column connected in series to the prepared ionexchange column. In this process, the strip solution volume comprisesaround 20 mL to around 40 mL. The strip solution may be added inmultiple smaller aliquots (e.g., 4×10 mL, 2×10 mL, etc.) or the stripsolution may be added all at once. The Fe in the strip solution binds tothe extractant (e.g., TBP) in the first column. The Ni in the stripsolution does not bind to the chromatographic resins and freely passesthrough both columns, while Cu and Co and other metals bind to the ionexchange column. The columns flow through volume may be collected as aNi recovery fraction.

The columns may be rinsed with an additional volume of HCl having thesame molarity as that of the strip solution to completely remove anyresidual Ni from the columns. For example, the columns may be rinsedwith about 8 mL to about 10 mL of 9 M HCl. For example, the columns maybe rinsed with about 8 mL of 9 M HCl. The volume of HCl may be added inmultiple smaller aliquots (e.g., 4×2 mL, 2×4 mL, etc.) or the volume ofHCl may be added all at once. The column flow through from the 9 M HClrinse may be collected and combined with the original Ni recoveryfraction. The combined Ni recovery fraction may be further processed torecover the ⁶⁴Ni, which then may be recycled and used for platingadditional cyclotron targets. Nickel recovery processes are well knownin the art. On average, in tracer studies that mimicked a ⁶⁴Cupurification, about 98% of the target Ni present in a simulated stripsolution may be recovered from the Ni recovery fraction. In variousembodiments, the percentage of Ni recovered in the recovery fraction mayrange from about 40% to about 99% of the starting Ni.

(ii) Removing ⁶¹Co

The separation process further comprises adding a volume of HCl having amolarity from about 3 M to about 6 M to the second column comprising theion exchange resin to elute ⁶¹Co (and metals other than Cu). In variousembodiments, a volume of 3 M HCl, 4 M HCl, 5 M HCl, or 6 M HCl may beadded to the ion exchange column. In specific embodiments, a volume(e.g., from about 10 mL to about 20 mL) of 4 M HCl may be added to theion exchange column. For example, about 10 mL of 4 M HCl may be added tothe ion exchange column. The eluent may be added in smaller aliquots(e.g., 5×2 mL, 3×3.33 mL, etc.) or the eluent may be added all at once.The ion exchange column eluate may be collected as a first wastefraction that mainly comprises ⁶¹Co.

The ion exchange column may be rinsed with an additional volume (e.g.,from about 8 mL to about 10 mL) of NaCl having a molarity of about 3 Mto 6 M in HCl having a molarity of about 0.01 M to about 3 M to eluteresidual ⁶¹Co. In specific embodiments, a volume (e.g., 8 mL) of 5 MNaCl in 0.05 M HCl may be added to the ion exchange column. The eluentmay be added in smaller aliquots (e.g., 4×2 mL, 2×4 mL, etc.) or theeluent may be added all at once. The ion exchange column eluate from the5 M NaCl eluent containing ⁶¹Co may be collected and combined with thefirst waste fraction containing ⁶¹Co.

Alternatively, the ion exchange column may be rinsed with an additionalvolume (e.g., from about 8 mL to about 10 mL) of HCl having a molarityfrom about 3 M to about 6 M to elute residual ⁶¹Co. In specificembodiments, a volume (e.g., 8 mL) of 4 M HCl may be added to the ionexchange column. The eluent may be added in smaller aliquots (e.g., 4×2mL, 2×4 mL, etc.) or the eluent mL may be added all at once. The ionexchange column eluate from the 5 M HCl eluent containing ⁶¹Co may becollected and combined with first waste fraction containing ⁶¹Co.

(iii) Isolating ⁶⁴Cu

The separation process further comprises adding a volume of HCl having amolarity from about 0.01 M to about 3 M to the ion exchange column toelute the ⁶⁴Cu. In certain embodiments, a volume of 0.05 HCl, 1 M HCl,2M HCl, or 3 M HCl may be added to the ion exchange column. In specificembodiments, the ⁶⁴Cu may be eluted from the ion exchange column with avolume of 0.05 M HCl. For example, about 10 mL of 0.05 M HCl may beadded to the ion exchange column. The eluent may be added in smalleraliquots (e.g., 5×2 mL, 4×2.5 mL, etc.) or the eluent may be added allat once. The eluate comprising ⁶⁴Cu is collected as the product of theprocess. On average, in tracer studies that mimicked a ⁶⁴Cupurification, about 89% of the Cu present in a simulated strip solutionmay be recovered in the eluate comprising Cu. In various embodiments,the percentage of ⁶⁴Cu recovered in the eluate comprising ⁶⁴Cu may rangefrom about 60% to about 100%. The ⁶⁴Cu in the eluate exists as[⁶⁴Cu]CuCl₂.

The final eluate comprising ⁶⁴Cu may be evaporated to dryness (or to asmaller volume) and the resultant residue may be reconstituted in avolume of HCl having a molarity about 0.001 M to about 1 M. In variousembodiments, the residue may be reconstituted in HCl having a molarityfrom about 0.005 M to about 0.5 M, from about 0.010 M to about 0.2 M,from about 0.025 M to about 0.1 M, or from about 0.04 M to about 0.06 M.In specific embodiments, the residue may be reconstituted in 0.05 M HClto form a final product comprising ⁶⁴Cu.

The ⁶⁴Cu compositions prepared by this process are described above insection (I).

(iv) Exemplary Extraction and Ion Exchange Chromatography PurificationProcess

The 9 M HCl strip solution is passed through a first column comprisingan extraction resin connected in series with a second column comprisinga weak anion exchange resin. The Fe in the strip solution binds to theextraction resin in the first column, ⁶⁴Cu and ⁶¹Co bind to the ionexchange resin in the second column, and ⁶⁴Ni flows through bothcolumns. The first and second columns are rinsed with 9M HCl to removeresidual ⁶⁴Ni. The initial column flow through and the 9 M HCL rinse canbe combined as the Ni recovery fraction. The ion exchange column isrinsed with 4 M HCl to elute the ⁶¹Co and then with 5 M NaCl in 0.05 MHCl or additional 4 M HCl to elute residual ⁶¹Co. Lastly, the ⁶⁴Cu iseluted from the ion exchange column with 0.05 M HCl.

(IV) Specific Compositions and Methods of the Disclosure

Accordingly, the present disclosure relates in particular to thefollowing non-limiting compositions and methods.

In a first composition, Composition 1, the present disclosure provides acomposition comprising from about 2 Ci to about 15 Ci of copper-64(⁶⁴Cu) and having a specific activity up to about 3800 mCi ⁶⁴Cu/μg Cu.

In another composition, Composition 2, the present disclosure provides acomposition comprising from about 2 Ci to about 15 Ci of ⁶⁴Cu at the endof bombardment (EOB) of a single cyclotron run.

In another composition, Composition 3, the present disclosure provides acomposition comprising from about 2 Ci to about 5 Ci of ⁶⁴Cu at EOB of asingle cyclotron run of about 2 h or about 4 h.

In another composition, Composition 4, the present disclosure provides acomposition comprising from about 5 Ci to about 9 Ci of ⁶⁴Cu at EOB of asingle cyclotron run of about 6 h.

In another composition, Composition 5, the present disclosure provides acomposition comprising up to about 15 Ci of ⁶⁴Cu at EOB of a singlecyclotron run of about 12 h

In another composition, Composition 6, the present disclosure provides acomposition, as provided in any one of Compositions 1 to 5, wherein thecomposition has a specific activity from about 140 mCi ⁶⁴Cu/μg Cu toabout 3800 mCi ⁶⁴CU/μg CU.

In another composition, Composition 7, the present disclosure provides acomposition, as provided in any one of Compositions 1 to 6, wherein thecomposition has a specific activity from about 350 mCi ⁶⁴Cu/μg Cu toabout 2300 mCi ⁶⁴CU/μg CU.

In another composition, Composition 8, the present disclosure provides acomposition, as provided in any one of Compositions 3 to 7, wherein thesingle cyclotron run comprises bombarding a nickel-64 target with a beamof protons having an energy of about 12 MeV to about 14 MeV.

In another composition, Composition 9, the present disclosure provides acomposition, as provided in any one of Compositions 1 to 8, wherein thecomposition has a total content of trace metals of less than about 5parts per million (ppm), the trace metals being cobalt, copper, gold,iron, lead, mercury, nickel, and zinc.

In another composition, Composition 10, the present disclosure providesa composition, as provided in any one of Compositions 1 to 9, whereinthe composition comprises a solution of hydrochloric acid (HCl).

In another composition, Composition 11, the present disclosure providesa composition, as provided in Composition 10, wherein the solutioncomprises about 0.001 M to about 3 M HCl.

In another composition, Composition 12, the present disclosure providesa composition, as provided in Compositions 10 or 11, wherein thesolution comprises about 2 M HCl.

In another composition, Composition 13, the present disclosure providesa composition, as provided in any one of Compositions 10 to 12, whereinthe solution comprises about 0.05 M HCl.

In another composition, Composition 14, the present disclosure providesa composition, as provided in any one of Compositions 10 to 13, whereinthe the ⁶⁴Cu exists as [⁶⁴Cu]CuCl₂.

In another composition, Composition 15, the present disclosure providesa composition, as provided in any one of Compositions 1 to 14, whereinthe composition further comprises a chelating agent or a bifunctionalchelating agent in which the ⁶⁴Cu is coordinated therein.

In another composition, Composition 16, the present disclosure providesa composition, as provided in Composition 15, wherein the chelatingagent or the bifunctional chelating agent is a macrocyclic compound, abridged macrocyclic compound, a bicyclic compound, or an acycliccompound.

In another composition, Composition 17, the present disclosure providesa composition, as provided in Compositions 15 or 16, wherein thebifunctional chelating agent is DOTA.

In another composition, Composition 18, the present disclosure providesa solution comprising (i) about 2 Ci to about 15 Ci of ⁶⁴Cu that has aspecific activity up to about 3800 mCi ⁶⁴Cu/μg Cu and (ii) HCl.

In another composition, Composition 19, the present disclosure providesa composition, as provided in Composition 18, wherein the specificactivity of the solution is from about 350 mCi ⁶⁴Cu/μg Cu to about 2300mCi ⁶⁴Cu/μg Cu.

In another composition, Composition 20, the present disclosure providesa composition, as provided in Compositions 18 or 19, wherein the HCl hasa concentration from about 0.001 M to about 3 M.

In another composition, Composition 21, the present disclosure providesa composition, as provided in any one of Compositions 18 to 20, whereinthe HCl has a concentration of about 0.5 M.

In another composition, Composition 22, the present disclosure providesa composition, as provided in any one of Compositions 18 to 21, whereinthe ⁶⁴Cu exists as [⁶⁴Cu]CuCl₂.

In another composition, Composition 23, the present disclosure providesa composition, as provided in any one of Compositions 18 to 22, whereinthe solution has a total content of trace metals of less than about 5ppm, the trace metals being cobalt, copper, gold, iron, lead, mercury,nickel, and zinc.

In another composition, Composition 24, the present disclosure providesa composition, as provided in any one of Compositions 18 to 23, whereinthe solution further comprises a chelating agent or a bifunctionalchelating agent in which the ⁶⁴Cu is coordinated therein.

In another composition, Composition 25, the present disclosure providesa composition, as provided in Composition 25, wherein the chelatingagent or the bifunctional chelating agent is a macrocyclic compound, abridged macrocyclic compound, a bicyclic compound, or an acycliccompound.

In another composition, Composition 26, the present disclosure providesa composition, as provided in Compositions 24 or 25, wherein thebifunctional chelating agent is DOTA.

In a first process, Process 1, the present disclosure provides a processfor preparing copper-64 (⁶⁴Cu) from nickel-64 (⁶⁴Ni), the processcomprising (a) bombarding a cyclotron target comprising ⁶⁴Ni with aproton beam to generate a bombarded target; (b) stripping the bombardedtarget with a volume of hydrochloric acid (HCl) having a molarity ofabout 6 M to about 12.1 M to form a strip solution comprising ⁶⁴Ni and⁶⁴Cu; and (c) purifying the ⁶⁴Cu from the strip solution by ion exchangechromatography comprising: (i) passing the strip solution through acolumn comprising an ion exchange resin such that ⁶⁴Cu binds to the ionexchange resin and ⁶⁴Ni passes through the column as a flow-through;(ii) rinsing the column with a volume of HCl having a molarity of about3 M to about 6 M; and (iii) adding a volume of HCl having a molarity ofabout 0.5 M to about 3 M to the column to elute the ⁶⁴Cu from the ionexchange resin and collecting an eluate comprising ⁶⁴Cu.

In another process, Process 2, the present disclosure provides aprocess, as provided in Process 1, wherein the cyclotron targetcomprises about 50 mg of ⁶⁴Ni plated in an area of about 4.0 cm².

In another process, Process 3, the present disclosure provides aprocess, as provided in Processes 1 or 2, wherein the proton beam has anenergy of about 10 MeV to about 14 MeV and a current of about 100 μA toabout 250 μA.

In another process, Process 4, the present disclosure provides aprocess, as provided in any one of Processes 1 to 3, wherein the protonbeam has an energy of about 12 MeV and a current up to about 225 μA.

In another process, Process 5, the present disclosure provides aprocess, as provided in any one of Processes 1 to 4, wherein thebombarding proceeds for about 1 h to about 6 h.

In another process, Process 6, the present disclosure provides aprocess, as provided in any one of Processes 1 to 5, wherein after thebombarding, the bombarded target comprises from about 2 Ci to about 12Ci of ⁶⁴Cu at the end of bombardment (EOB).

In another process, Process 7, the present disclosure provides aprocess, as provided in Process 6, wherein after about 2 h to about 4 hof bombarding, the bombarded target comprises from about 2 Ci to about 5Ci of ⁶⁴Cu at EOB.

In another process, Process 8, the present disclosure provides aprocess, as provided in Process 6, wherein after about 6 h ofbombarding, the bombarded target comprises from about 5 Ci to about 9 Ciof ⁶⁴Cu at EOB.

In another process, Process 9, the present disclosure provides aprocess, as provided in any one of Processes 1 to 8, wherein thestripping of the bombarded target is conducted at a temperature of about65° C. to about 100° C.

In another process, Process 10, the present disclosure provides aprocess, as provided in any one of Processes 1 to 9, wherein thestripping comprises contacting the bombarded target three times with analiquot of 9 M HCl for about 3-5 minutes each time, and collecting thealiquots as the strip solution.

In another process, Process 11, the present disclosure provides aprocess, as provided in any one of Processes 1 to 10, wherein thebombarded target is rinsed with an additional aliquot of 9 M HCl, whichis then added to the strip solution.

In another process, Process 12, the present disclosure provides aprocess, as provided in any one of Processes 1 to 11, wherein the ionexchange resin is a strong anion exchange resin comprisingtrimethylbenzyl ammonium chloride groups.

In another process, Process 13, the present disclosure provides aprocess, as provided in any one of Processes 1 to 12, wherein theflow-through from passing the strip solution through the column iscollected as a ⁶⁴Ni recovery fraction.

In another process, Process 14, the present disclosure provides aprocess, as provided in any one of Processes 1 to 13, wherein afterpassing the strip solution through the column, a further volume of 9 MHCl is added to the column and its flow-through is combined with the⁶⁴Ni recovery fraction.

In another process, Process 15, the present disclosure provides aprocess, as provided in Process 14, wherein an average of about 82% ofthe target ⁶⁴Ni is recovered in the ⁶⁴Ni recovery fraction.

In another process, Process 16, the present disclosure provides aprocess, as provided in any one of Processes 1 to 15, wherein therinsing comprises adding 4 M HCl to the column to elute cobalt, which iscollected as a waste fraction.

In another process, Process 17, the present disclosure provides aprocess, as provided in any one of Processes 1 to 16, wherein the ⁶⁴Cuis eluted form the column with 2 M HCl.

In another process, Process 18, the present disclosure provides aprocess, as provided in any one of Processes 1 to 17, wherein an averageof about 80% of the ⁶⁴Cu present in the strip solution is recovered inthe eluate comprising ⁶⁴Cu.

In another process, Process 19, the present disclosure provides aprocess, as provided in any one of Processes 1 to 18, wherein the eluatecomprising ⁶⁴Cu is evaporated to dryness and reconstituted in 0.05 MHCl, thereby forming a final product comprising ⁶⁴Cu.

In another process, Process 20, the present disclosure provides aprocess, as provided in Process 19, wherein the final product comprising⁶⁴Cu comprises from about 2 Ci to about 12 Ci of ⁶⁴Cu.

In another process, Process 21, the present disclosure provides aprocess, as provided in Processes 19 or 20, wherein the final productcomprising ⁶⁴Cu has a specific activity up to about 3800 mCi ⁶⁴Cu/μg Cu.

In another process, Process 22, the present disclosure provides aprocess, as provided in any one of Processes 19 to 21, wherein the finalproduct comprising ⁶⁴Cu has a specific activity from about 350 mCi⁶⁴Cu/μg Cu to about 2300 mCi ⁶⁴Cu/μg Cu.

In another process, Process 23, the present disclosure provides aprocess, as provided in any one of Processes 19 to 22, wherein the finalproduct comprising ⁶⁴Cu has a total content of trace metals of less thanabout 5 ppm, the trace metals being cobalt, copper, gold, iron, lead,mercury, nickel, and zinc.

In another process, Process 24, the present disclosure provides anadditional process for preparing copper-64 (⁶⁴Cu) from nickel-64 (⁶⁴Ni),in which the ⁶⁴Cu is purified by a combination of extractionchromatography and ion exchange chromatography. The process comprises(a) bombarding a cyclotron target comprising ⁶⁴Ni with a proton beam togenerate a bombarded target; (b) stripping the bombarded target with avolume of HCl having a molarity of about 6 M to about 12.1 M to form astrip solution comprising ⁶⁴Ni, ⁶⁴Cu, ⁶¹Co, and one or more tracemetals; and (c) purifying the ⁶⁴Cu from the strip solution bychromatography, wherein the chromatography comprises (i) passing thestrip solution through a first column comprising an extraction resinconnected in series to a second column comprising an ion exchange resin,such that the one or more trace metals binds to the extraction resin inthe first column, ⁶⁴Cu and ⁶¹Co bind to the ion exchange resin in thesecond column, and ⁶⁴Ni passes through both columns as a firstflow-through fraction. The process further comprises (ii) rinsing thefirst and second columns with a volume of HCl having a molarity of about6 M to about 12.1 M to remove residual ⁶⁴Ni as a second flow-throughfraction; (iii) rinsing the second column with a volume of HCl having amolarity of about 3 M to about 6 M to elute ⁶¹Co as a first wastefraction; (iv) rinsing the second column with a volume of NaCl having amolarity of about 3 M to 6 M in HCl having a molarity of about 0.01 M toabout 3 M to elute residual ⁶¹Co as a second waste fraction or rinsingthe second column with an additional volume of HCl having a molarity ofabout 3 M to about 6 M to elute ⁶¹Co as a second waste fraction; and (v)adding a volume of HCl having a molarity of about 0.01 M to about 3 M tothe second column to elute the ⁶⁴Cu as a product fraction comprising⁶⁴Cu.

In another process, Process 25, the present disclosure provides aprocess, as provided in Process 24, wherein the cyclotron target at (a)comprises about 750 mg of ⁶⁴Ni plated in an area of about 23.0 cm².

In another process, Process 26, the present disclosure provides aprocess, as provided in Processes 24 or 25, wherein the proton beam at(a) has an energy of about 10 MeV to about 15 MeV and a current of about350 μA to about 408 μA.

In another process, Process 27, the present disclosure provides aprocess, as provided in any one of Processes 24 to 26, wherein theproton beam at (a) has an energy of about 13 MeV and a current of about350 μA to about 408 μA.

In another process, Process 28, the present disclosure provides aprocess, as provided in any one of Processes 24 to 27, wherein thebombardment (a) proceeds for about 12 h to about 24 h, and the bombardedtarget comprises from about 46 Ci to about 82 Ci of ⁶⁴Cu at the end ofbombardment (EOB).

In another process, Process 29, the present disclosure provides aprocess, as provided in Processes 28, wherein after about 16 h to about20 h of bombarding at (a), the bombarded target comprises from about 56Ci to about 75 Ci of ⁶⁴Cu at EOB.

In another process, Process 30, the present disclosure provides aprocess, as provided in Processes 28, wherein after about 19 h ofbombarding at (a), the bombarded target comprises from about 62 Ci toabout 73 Ci of ⁶⁴Cu at EOB.

In another process, Process 31, the present disclosure provides aprocess, as provided in any one of Processes 24 to 30, wherein thestripping at (b) comprises contacting the bombarded target with 9 M HCl,and the stripping at (b) is conducted at a temperature of about 65° C.to about 100° C.

In another process, Process 32, the present disclosure provides aprocess, as provided in any one of Processes 24 to 31, wherein theextraction resin in the first column at (c)(i) comprisestributylphosphate as a functional group, and the ion exchange resin inthe second column at (c)(i) comprises a tertiary amine as a functionalgroup.

In another process, Process 33, the present disclosure provides aprocess, as provided in any one of Processes 24 to 32, wherein therinsing at (c)(ii) comprises 9 M HCl.

In another process, Process 34, the present disclosure provides aprocess, as provided in any one of Processes 24 to 33, wherein the firstand second flow-through fractions are combined as a ⁶⁴Ni recoveryfraction.

In another process, Process 35, the present disclosure provides aprocess, as provided in Process 34, wherein an average of about 98% ofthe target ⁶⁴Ni is recovered in the ⁶⁴Ni recovery fraction.

In another process, Process 36, the present disclosure provides aprocess, as provided in any one of Processes 24 to 35, wherein therinsing at (c)(iii) comprises 4 M HCl, and the rising at (c)(iv)comprises 5 M NaCl in 0.05 M HCl or additional 4 M HCl.

In another process, Process 37, the present disclosure provides aprocess, as provided in any one of Processes 24 to 36, wherein the ⁶⁴Cuis eluted at (c)(v) with 0.05 M HCl.

In another process, Process 38, the present disclosure provides aprocess, as provided in any one of Processes 24 to 37, wherein anaverage of about 89% of the ⁶⁴Cu present in the strip solution isrecovered in the product fraction comprising ⁶⁴Cu.

In another process, Process 39, the present disclosure provides aprocess, as provided in any one of Processes 24 to 38, wherein theproduct fraction comprising ⁶⁴Cu comprises from about 2 Ci to about 15Ci of ⁶⁴Cu and has a specific activity up to about 3800 mCi ⁶⁴Cu/μg Cu.

In another process, Process 40, the present disclosure provides aprocess, as provided in any one of Processes 24 to 39, wherein theproduct fraction comprising ⁶⁴Cu has a total content of trace metals ofless than about 5 ppm, the trace metals being cobalt, copper, gold,iron, lead, mercury, nickel, and zinc.

Definitions

The features, structures, steps, or characteristics disclosed herein inconnection with one embodiment may be combined in any suitable manner inone or more alternative embodiments.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

The terms “about” and “substantially” preceding a numerical valuemean±10% of the recited numerical value.

Where a range of values is provided, each value between the upper andlower ends of the range are specifically contemplated and describedherein.

The term “carrier,” as used herein refers to an inactive materialdeliberately added to a specified radioactive substance to ensure thatthe radioactivity will behave normally in all subsequent chemical andphysical processes.

The term “non-carrier added” refers to a preparation of a radioactiveisotope which is ‘free’ from stable isotopes of the element in question.More precisely, a preparation of a radioactive isotope of high specificactivity to which no isotopic carrier was intentionally added and whichwas not produced by irradiation of a stable isotope of the same element.

EXAMPLES

The following examples illustrate various non-limiting embodiments ofthe present disclosure.

Example 1: Separation of Metals Via Ion Exchange Chromatography

According to the literature, a bombarded Ni target typically isdissolved in 6 M hydrochloric acid (HCl) and the resulting solution ispurified via anion exchange chromatography. After the nickel hascompletely eluted from the column, the eluent is changed to low molarityHCl (often s 0.5 M) or water and the copper is collected as it isreleased from column. However, ⁶⁴Cu prepared this way typically containssome ⁶¹Co, as Co elutes from the resin in 4 M HCl. Thus, to obtainbetter separation of Co and Cu, a trial separation of various metals wasperformed using solutions of 6 M, 4 M, and 2 M HCl to elute Ni, Co, andCu, respectively.

A solution containing 5.0 mg/mL Ni and 25 μg/mL each of Co, Cu, Fe, Zn,Hg and Pb in 6 M HCl was prepared to mimic an un-purified mixture. Aglass Econo-column (0.7 cm×20 cm) was dry-packed with 4.5 g of AG 1-X8resin (16 cm bed height, 6 mL bed volume). The resin was pre-treated bywashing the column with 30 mL of Chelex-treated H₂O followed by 30 mL of6 M HCl. This rinse cycle was repeated once more so that the final washwas with 6 M HCl. The columns were gravity drained and each wash wasconsidered complete once droplet formation ceased.

The column was loaded with 10 mL of the metal solution (50 mg Ni, 250 μgeach added metal) and the flow through was collected as 2×5 mL fractions(load fraction). The column was eluted with the following: 5×2 mLaliquots of 6 M HCl (6 M fraction), 5×2 mL aliquots of 4 M HCl (4 Mfraction), 5×2 mL aliquots of 2 M HCl (2 M fraction), and 1×5 mL aliquotof 0.5 M HCl (0.5 M fraction). Each eluate and an aliquot of the initialunpurified mixture were analyzed by Inductively Coupled Plasma OpticalEmission Spectroscopy (ICP-OES). Table 1 presents the amount of metalpresent in each fraction as a percentage of what was present in theinitial unpurified mixture.

TABLE 1 Percent of metal in each fraction. Load 6M 4M 2M 0.5M Ni 89.531.9 0.0 0.0 0.0 Co 36.5 46.5 16.7 0.0 0.0 Cu 0.0 0.0 9.6 80.6 0.1 Fe0.0 0.0 0.0 10.7 40.7 Hg 0.0 0.0 0.0 0.0 0.0 Pb 0.4 7.2 44.0 20.0 6.4 Zn36.9 13.1 0.0 0.0 0.0

As expected, Ni was present in the load fraction and the 6 M HClfraction. The majority of Cu was present in 2 M HCl fraction, with asmall amount (9.6%) present in the 4 M HCl fraction. Co was observed inthe load, 6 M HCl, and 4 M HCl fractions, with no co-elution with Cu inthe 2 M HCl fraction. Thus, there was good separation of Ni and Co fromCu, with 80.6% of the total Cu collected in the 2 M HCl faction with noco-elution of either Ni or Co. The only other tested metals present inthe 2 M HCl fraction were small percentages of Pb and Fe.

Example 2: Varying Molarity of Starting Acid

To determine whether early breakthrough of Co could be reduced, as wellas Pb breakthrough in the 2 M HCl fraction, the molarity of the startingacid was increased to 9 M HCl.

A solution containing 5.0 mg/mL Ni and 25 μg/mL each of Co, Cu, Fe, Zn,Hg and Pb in 9 M HCl was prepared. A column comprising 4.5 g of AG 1-X8resin was prepared described above in Example 1. The column resin waspre-treated with 30 mL of Chelex-treated H₂O followed by 30 mL of 9 MHCl. This rinse cycle was repeated once more so that the final wash waswith 9 M HCl. The prepped column was loaded with 10 mL of the Nisolution (50 mg Ni, 250 μg each added metal) and collected as 2×5 mLfractions. The column then was eluted, and fractions collected with thefollowing: 5×2 mL fractions of 9 M HCl, 5×2 mL fractions of 4 M HCl, 5×2mL fractions of 2 M HCl, and 1×5 mL of 0.5 M HCl. Samples of the eluatesand the initial unpurified mixture were analyzed via ICP-OES. These dataare presented in Table 2.

TABLE 2 Percent of metal in each fraction. Load 9M HCl 4M HCl 2M HCl0.5M HCl Ni 78.7 27.6 0 0 0 Co 3.1 0.9 94.0 0.3 0 Cu 0 0 2.1 93.0 0.1 Fe0 0 0 9.0 41.4 Hg 0 0 0 0 0 Pb 10.6 83.2 4.7 0.1 0 Zn 36.8 12.9 0 0 0

The use of 9 M HCl as the starting acid concentration improved theoverall separation process by shifting the elution profiles of Co andPb. The majority of Co was eluted in the 4 M HCl fraction (rather thanthe earlier fractions), and the majority of Pb was eluted in the loadand 9 M HCl fractions (rather than the 4 M HCl fraction). The 2 M HClfraction contained mainly Cu with a low percentage of Fe and traceamounts of Co and Pb.

Example 3: Adjusting a CS-30 Cyclotron to Reduce Proton Beam Energy

Copper-64 may be produced by bombarding enriched nickel-64 with lowenergy protons (e.g., less than 14 MeV). At higher beam energies, theproduction of ⁶¹Co and stable ⁶³Cu increases and ⁶⁴Cu productiondecreases, therefore ⁶⁴Cu production from ⁶⁴Ni via the (p,n) reaction isbest performed with 12 MeV protons.

It has been generally assumed that CS-30 cyclotrons were not suitablefor ⁶⁴Cu production because they may accelerate a proton beam up toabout 30 MeV. It is generally accepted that a cyclotron cannot attain abeam energy lower than half of its maximum energy. Thus, the lowestenergy attainable in CS-30 cyclotrons, in theory, is about 15 MeV.

The output energy of a cyclotron is given by the equation E=(rqB)²/2 m,where E is the particle energy, r is the radius at which the targets areinserted, q is the charge on the particle of interest, B is the magneticfield, and m is the mass of the particle being accelerated. Sinceprotons are being accelerated, the mass and charge are 1.672×10⁻²⁷ kg,and 1.602×10⁻¹⁹ C, respectively. The magnetic field used in CS-30cyclotrons is 1.847 T. FIG. 3 shows the proton energy as a function ofthe proton beam radius. This plot predicts a target radius of about 27.9cm to attain a beam energy of about 12 MeV.

Thus, in order to produce the desired proton beam energy of 12 MeV, thelocation of the target was adjusted in the cyclotron so that the protonbeam would strike the target at the smaller radius of about 27.9 cm.

Initial beam strikes with CS-30 curved targets showed that the protonbeam went too far along one edge of the target, all of the way to theend, with no beam on the majority of the target face, completely missingthe opposite edge. Only about 25% of the entire target face had beam onit, and half of that was on an unusable edge. With this arrangement, toomuch of the beam would be lost, and hence it is unsuitable. This wasremedied by substituting a flat target for the curved one. Using a flattarget allowed the beam to strike about one-fifth of the total targetarea (e.g., about one-fifth from the end of the target). The total areacovered by the beam was 4 cm². The beam strike from the flat target wasacceptable. Tuning parameters of the CS-30 were determined to give thebest beam strike at the new radius of 27.9 cm. Thus, by using a flattarget, the target radius was reduced, and the energy of the proton beamcould be reduced to about 12 MeV.

Example 4: Target Bombardments of Enriched Nickel-64

A CS-30 cyclotron adjusted as described above in Example 3 was used toproduce ⁶⁴Cu. For this, about 50 mg of ⁶⁴Ni (˜99% isotopically enriched)was electroplated on a CS-30 cyclotron flat target comprising a copperbase layer that had been electroplated with gold to a thickness of about50 μm. The plated area was about 4.0 cm². The target was bombarded witha beam energy of about 12 MeV, a beam current of 200 μA or 225 μA, andbombardment time of 1 to 6 h. The target was stripped with 9 M HCl andthe resultant solution was analyzed by HPGe gamma spectroscopy todetermine ⁶⁴Cu yield at the end of bombardment (EOB). Table 3 showsresults of preliminary runs.

TABLE 3 Yield of Test Runs. Beam Bombardment ⁶⁴Cu Activity, Run CurrentTime calibrated to EOB 1 200 μA 1 h 674.1 mCi 2 200 μA 6 h 6,102 mCi 3225 μA 1 h 1,424.8 mCi 4 225 μA 6 h 6,900.1 mCi

Example 5: Purification of Copper-64 from a Bombarded Nickel-64 Target

Flat CS-30 cyclotron targets that had been electroplated with 50 μm ofgold, were plated with enriched ⁶⁴Ni, targeting a mass of about 50 mgand a plated area of 4.0 cm². The target was bombarded for 1 to 6 h witha beam energy of about 12 MeV and beam current of approximately 200 μAor 225 μA. The bombarded target was stripped using three 3.0 mL aliquotsof 9 M HCl. During this time, the target stripping cell was heated to75° C., and each aliquot was held 3-5 minutes. After the hold time, the3-mL aliquot was removed and placed in a holding vessel. The aliquotswere collected together as one, approximately 9 mL strip solution.

The ⁶⁴Cu was isolated and purified by anion exchange chromatographyessentially as described above in Example 2. For this, a glassion-exchange column (inner diameter=1.0 cm, length=20 cm) was nitricacid washed, rinsed with high resistivity water, and packed with 4.5 gAG 1-X8 resin (chloride form), 100 to 200 mesh (8 cm bed height, 6 mLbed volume). The column resin was pre-treated by washing twice withChelex-treated 18.2 MΩ·cm resistivity water followed by 9 M HCl.

The 9-mL strip solution was loaded onto a pre-treated ion-exchangecolumn along with an additional 1 mL of 9 M HCl that was used to rinsethe vessel holding the strip solution. The 10-mL load volume was elutedfrom the column by gravity at ˜1 mL per minute as the load fraction.Gravity filtration was used for all the solutions that passed throughthe column. The column was then rinsed with another 10 mL of 9 M HCl andthe eluate was combined with the load fraction. The combined fractions(approximately 20 mL) comprised the ⁶⁴Ni recovery fraction. After the⁶⁴Ni recovery fraction was collected from the column, 10 mL of 4 M HClwas added to the column. The eluate comprising cobalt was collectedseparately as a waste fraction. After the 4 M HCl fraction was collectedfrom the column, 8 mL of 2 M HCl was added to the column. The 2 M HCleluate collected in a separate vial and contained the ⁶⁴Cu product. The2 M HCl eluate was evaporated to dryness and reconstituted in 0.05 M HClto a target radioactive concentration of approximately 1.25 Ci/mL.

Aliquots of the strip solution and the eluates were analysed by gammaspectroscopy and/or with a dose calibrator to determine ⁶⁴Cu activity,and via ICP-OES to determine metallic content. The yield of ⁶⁴Cu at EOBfor 15 runs ranged from 674 mCi (1 h bombardment at 200 μA) to 8,706 mCi(6 h bombardment at 200 μA). The average yield of ⁶⁴Cu at EOB for 8 runsthat had a bombardment time of 6 h and beam current of 200-225 μA was67132.6 mCi (s.d.=1189.1). The average recovery of ⁶⁴Cu in the 2 M HCleluate (relative to the strip solution) for the 15 runs was about 80%(s.d.=20%). After reconstituting the ⁶⁴Cu in 0.05 M HCl, the resultingspecific activity of the [⁶⁴Cu]CuCl₂ averaged 965.8 mCi ⁶⁴Cu/μg Cu(s.d.=658) at EOB when measured by the dose calibrator, and 1,724.2 mCi⁶⁴Cu/μg Cu (s.d.=750) at EOB when measured by the HPGe detector. The Cucontent was determined via ICP-OES. Further analysis revealed nostatistically significant difference between the dose calibrator and theHPGe detector. The dose calibrator method was preferred because it wasmore straightforward to use during manufacturing. The average recoveryof ⁶⁴Ni (in the ⁶⁴Ni recovery fraction) from the 15 processed targetswas about 82%.

Presented below is a detailed analysis of the purified product fromthree representative runs. For these runs, the target was bombarded for6 h with a beam energy of approximately 12 MeV and beam current of 200or 225 μA. Total activity was measured with a dose calibrator calibratedfor ⁶⁴Cu. Table 4 shows the activity of ⁶⁴Cu collected after thepurification process. Table 4 also shows the purification process yieldsas amount of ⁶⁴Cu per total activity of the strip solution (asdetermined by dose calibrator).

TABLE 4 Recovery of ⁶⁴Cu During Purification Batch 1 Batch 2 Batch 3Strip Solution (mCi) 9,872.0 10,625 10,798 2M HCl Eluate (mCi) 6,154.48,385 8,760 % ⁶⁴Cu recovery 62.3% 78.9% 81.1%

Table 5 presents the levels of trace metals in the 2 M HCl eluate.

TABLE 5 Trace Metal Analysis in 2M HCl Eluate Batch 1 Batch 2 Batch 3 Au(μg/mL) 0 0 0 Co (μg/mL) 0 0 0.047 Cu (μg/mL) 0.343 0.745 0.673 Fe(μg/mL) 0.102 0.117 0.261 Hg (μg/mL) 0 0 0 Ni (μg/mL) 0.434 0.403 0.484Pb (μg/mL) 0.031 0.031 0.886 Zn (μg/mL) 0.114 1.899 2.448

Table 6 presents the specific activity of the ⁶⁴Cu product in the 0.05 MHCl solution.

TABLE 6 Specific Activity of ⁶⁴Cu in 0.05M HCl Solution Batch 1 Batch 2Batch 3 ⁶⁴Cu activity (i)mC 4,041.1 7,650.0 8,109.0 Cu mass (μg) 2.0 8.25.7 Specific Activity (mCi ⁶⁴Cu/μg Cu) 2,010.5 937.6 1,425.2

Example 6. Separation of Metals Via Extraction and Ion ExchangeChromatography

A trial separation of various metals was performed using a combinationof extraction chromatography and ion exchange chromatography to moreeffectively separate Cu from masses of Ni up to 750 mg, Co, Fe, andother transition metals.

A polyethylene (PE) column (0.7 cm×20 cm) was vacuum-packed using 20 mLof 0.05 M HCl with 2.7 g of TK201 resin (about 5 cm to 6 cm bed height,about 1 mL to 2 mL bed volume). A PE frit was securely placed atop thepacked resin bed. The packed PE column, containing TK201 resin, wasrinsed with 20 mL of 0.05 M HCl under vacuum. The packed PE column wascapped and stored at 4.4° C.

The pre-packed PE column containing 2.7 g of TK201 resin, stored in 0.05M HCl at 4.4° C., and a 2 mL PE column containing 300 mg of TBP resinwere pre-treated by washing each column with 10 mL of high-resistivitywater (HRW) followed by 10 mL of 9 M HCl. The HRW and 9 M HCl werepassed through each column at a flow-rate of 1 mL/min using a syringepump. Each wash was considered complete once droplet formation ceased.

A solution containing 25.0 mg/mL Ni, 20.4 μg/mL Co, 8.6 μg/mL Cu, 8.1μg/mL Fe, and 10.3 μg/mL Pb was prepared in 9 M HCl to simulate abombarded target stripping solution.

The PE columns, connected in series, were loaded at a flow-rate of 1mL/min using a syringe pump with 30 mL of the metal solution (746 mg Ni,259 μg Cu, 611 μg Co, 244 μg Fe, 309 μg Pb) and the flow through wascollected as a single 30 mL fraction (load fraction). The two columnswere eluted with 2×4 mL aliquots of 9 M HCl (9 M fraction) and the flowthrough was collected. The ion exchange column was then eluted with thefollowing: 2×5 mL aliquots of 4 M HCl (4 M fraction), 2×4 mL aliquots of5 M NaCl in 0.05 M HCl (5 M NaCl fraction), and 2×5 mL aliquot of 0.05 MHCl (0.05 M fraction). Each eluate and an aliquot of the initial mixturewere analyzed by Inductively Coupled Plasma Optical EmissionSpectroscopy (ICP-OES). Table 7 presents the amount of metal present ineach fraction as a percentage of the starting amount in the simulatedstripping solution mixture.

TABLE 7 Percentages of Various Metals in Each Fraction Element Load 9MHCl 4M HCl 5M NaCl 0.05M HCl Co 53.5 7.0 21.6 11.4 n.d.* Cu n.d. n.d.n.d. n.d. 86.5 Ni 88.3 10.1 0.03 n.d. n.d. Fe n.d. n.d. n.d. n.d. n.d.Pb 75.4 11.4 0 0 0 *n.d. = not detected or below the limits of detection

As expected, Ni was present in the load fraction and the 9 M HCl rinsefraction (98.4%). The Cu was measured only in the 0.05 M HCl fraction(86.5%). Co was observed in the load, 9 M HCl, 4 M HCl, and 5 M NaClfractions, with no co-elution of Cu in the 0.05 M HCl fraction. Thus,there was good separation of Ni and Co from Cu, with 86.5% of the totalCu collected in the 0.05 M HCl faction with no co-elution of either Nior Co.

What is claimed is:
 1. A composition for use as a radioactive precursorcomprising from 2 Ci to 15 Ci of copper-64 (⁶⁴Cu), wherein theradionuclidic purity of the ⁶⁴Cu is greater than 98.5%.
 2. Thecomposition of claim 1, wherein the radionuclidic purity of the ⁶⁴Cu isgreater than 99%.
 3. The composition of claim 1, wherein theradionuclidic purity of the ⁶⁴Cu is greater than 99.5%.
 4. Thecomposition of claim 1, wherein the radionuclidic purity of the ⁶⁴Cu isgreater than 99.9%.